: Metastatic castration-resistant prostate cancer (mCRPC) is, at present, almost invariably fatal. There is an urgent need to tailor mCRPC therapy to vulnerabilities present within individual tumors. Crosstalk between DNA damage response and androgen receptor (AR) signaling represents one of the most promising opportunities for personalizing prostate cancer therapy. In this application, we will investigate the mechanistic and therapeutic implications of alterations in the three most commonly altered DNA repair genes in mCRPC: BRCA2, BRCA1, and ATM. Using novel in vitro and in vivo models of homologous recombination (HR) deficiency, we will interrogate the impact of BRCA2 vs. BRCA1 vs. ATM alterations, two copy vs. one copy aberrations, and truncating vs. non-truncating mutations on homologous recombination, androgen receptor (AR) signaling, and response to PARP inhibitors or AR- directed therapies. We will then validate these findings in unique cohorts of mCRPC patients treated with these agents. Finally, we will use CRISPR-based functional genomic approaches to identify novel genetic vulnerabilities in mCPRC models that can inform the next generation of therapeutic strategies and guide the development of clinical trials. Our study will significantly advance the mCRPC field by: 1) developing the first human preclinical models of HR deficiency, 2) functionally characterizing the most prevalent BRCA2, BRCA1, and ATM alterations in mCRPC, 3) better defining the mechanistic pathways that define the response of mCRPC to PARPi and AR-directed therapies, and 4) discovering novel targets that influence these responses. Given the prevalence of BRCA2, BRCA1, and ATM alterations in other cancers, including breast, ovarian, and pancreatic adenocarcinomas, the mechanisms uncovered by these studies will have clinical implications far beyond the mCRPC space, and will represent an advance towards individualizing cancer therapy based on tumor genetic alterations.